Malignant gliomas, in particular grade IV glioblastoma multiforme, have a very poor prognosis that has failed to improve significantly over the past three decades. Elucidation of the biology of this disease will aid in the development of novel therapies. I propose to design, construct, and pre-clinically evaluate recombinant cytotoxic proteins targeted specifically to malignant glioma cells. These recombinant proteins will be targeted to the EphA2 receptor. A member of the Eph receptor tyrosine kinases, EphA2 has been shown to be overexpressed and functionally important in several epithelial malignancies, but has never been investigated in brain cancer. The recombinant proteins will consist of a bacterial cytotoxin linked to the endogenous ligand for EphA2, ephrinA1. Because malignant glioma cells highly overexpress the receptor, the drug will be targeted to these cells while avoiding normal cells, which have undetectable levels of EphA2. These drugs will be produced and evaluated for their binding properties, localization, and anti-tumor efficacy. The functional significance of the EphA2/ephrinA1 system will be investigated for its role in GBM pathobiology and potentially aid in the design of targeted therapeutics. [unreadable] [unreadable] [unreadable] [unreadable]